Tryptase inhibitors

ABSTRACT

A compound of formula I                    
     in which M, A1, A2, A3, A4, A5, A6, B1, B2, B3, B4, B5, B6, K1, and K2 are defined herein and are novel effective tryptase-inhibitors.

FIELD OF APPLICATION OF THE INVENTION

The invention relates to novel tryptase inhibitors which are used in thepharmaceutical industry for preparing medicaments.

KNOWN TECHNICAL BACKGROUND

The international applications WO95/32945, WO96/09297, WO98/04537,WO99/12918 and WO99/24395 describe low-molecular-weight compounds foruse as tryptase inhibitors.

DESCRIPTION OF THE INVENTION

It has now been found that the compounds of the formula I, which aredescribed in more detail below, have surprising and particularlyadvantageous properties.

The invention provides compounds of the formula I

in which

A1 and A2 are identical or different and are —C(O)—, —NH—, —O— (oxygen),—S— (sulfur), —S(O)₂—, —S(O)₂—NH—, —NH—S(O)₂—, —C(O)—NH—, —NH—C(O)—,—O—C(O)—, —C(O)—O— or a bond,

A3 and A4 are identical or different and are —C(O)—, —O—, —S—, —NH—,—O—C(O)—, —C(O)—O—, —C(O)—NH—, —NH—C(O)— or a bond, or are selected fromthe group consisting of

where

E is —O— (oxygen), —S— (sulfur) or —CH₂— (methylene),

G is —O— (oxygen) or —CH₂— (methylene), and

T is the group —C(O)— or a bond,

A5 and A6 are identical or different and are —C(O)—, —NH—, —O—, —S—,—C(O)—NH—, —NH—C(O)—, —O—C(O)—, —C(O)—O—, —NH—C(O)—NH— or a bond,

M is the following central building block

K1 is —B7-(C(O))_(m)—B9-X1, —B7-(C(O))_(m)—B9-Y1 or—B7-(C(O))_(m)—B9-Z1-B11-X1,

K2 is —B8-(C(O))_(p)—B10-X2, —B8-(C(O))_(p)—B10-Y2 or—B8-(C(O))_(p)—B10-Z2-B12-X2,

B1, B2, B3, B4, B5 and B6 are identical or different and are a bond or1-4C-alkylene,

B7, B8, B9, B10, B11 and B12 are identical or different and are a bondor 1-4C-alkylene,

m is 0 or 1,

p is 0 or 1,

X1 and X2 are identical or different and are selected from the followinggroups

where

R8 is 1-4C-alkyl,

Y1 and Y2 are identical or different and are a 4-11C-heteroaryl or2-7C-heterocycloalkyl radical containing at least one ring nitrogen,

Z1 and Z2 are identical or different and are 5-12C-arylene,5-12C-heteroarylene, 3-8C-cycloalkylene 3-8C-heterocycloalkylene,

where each arylene, heteroarylene, cycloalkylene, heterocycloalkylene,heteroaryl or heterocycloalkyl may additionally for its part besubstituted by one, two or three substituents selected from the groupconsisting of hydroxyl, halogen, nitro, cyano, amino, 1-4C-alkyl,1-4C-alkoxy, 1-4C-alkoxycarbonyl, 1-4C-alkylcarbonyloxy, carboxyl oraminocarbonyl,

and where on the direct route between the terminal nitrogen atoms 20 to40, preferably 25 to 40, bonds have to be present,

the salts of these compounds, and the N-oxides of thenitrogen-containing heteroaryls, heterocycloalkyls, heteroarylenes andheterocycloalkylenes, and their salts, where all those compounds areexcluded in which one or more of the variables B1, B2, B3, B4, B5, B6,B7, B8, B9, B10, B11 or B12 may assume the meaning of a bond resultingin the direct linkage of two heteroatoms or two carbonyl groups.

1-4C-Alkyl represents straight-chain or branched alkyl radicals having 1to 4 carbon atoms. Examples which may be mentioned are the butyl,isobutyl, sec-butyl, tert-butyl, propyl, isopropyl, ethyl and the methylradicals.

1-4C-Alkoxy represents radicals which, in addition to the oxygen atom,contain a straight-chain or branched alkyl radical having 1 to 4 carbonatoms. Examples which may be mentioned are the butoxy, isobutoxy,sec-butoxy, tert-butoxy, propoxy, isopropoxy and preferably the ethoxyand methoxy radicals.

1-4C-Alkoxycarbonyl represents a carbonyl group to which is attached oneof the above-mentioned 1-4C-alkoxy radicals. Examples which may bementioned are the methoxycarbonyl [CH₃O—C(O)—] and the ethoxycarbonyl[CH₃CH₂O—C(O)—] radicals.

1-4C-Alkylcarbonyloxy represents a carbonyloxy group to which isattached one of the above-mentioned 1-4C-alkyl radicals. An examplewhich may be mentioned is the acetoxy [CH₃C(O)—O—] radical.

For the purpose of the invention, halogen is bromine, chlorine andfluorine.

1-4C-Alkylene represents straight-chain or branched 1-4C-alkyleneradicals, for example the methylene (—CH₂—), ethylene (—CH₂—CH₂—),trimethylene (—CH₂—CH₂—CH₂—), tetramethylene (—CH₂—CH₂—CH₂—CH₂—),1,2-dimethylethylene [—CH(CH₃)—CH(CH₃)—], 1,1-dimethylethylene[—C(CH₃)₂—CH₂—], 2,2-dimethylethylene [—CH₂—C(CH₃)₂—], isopropylidene[—C(CH₃)₂—] or the 1-methylethylene [—CH(CH₃)—CH₂—] radicals.

If m is 0, the group —(C(O))_(m)— is a bond.

If p is 0, the group —(C(O))_(p)— is a bond.

4-11C-Heteroaryl represents a—if desired substituted—mono- or bicyclicaromatic hydrocarbon which contains 4 to 11 carbon atoms and at leastone ring nitrogen atom; in addition, one or more of the carbon atoms maybe replaced by ring heteroatoms selected from the group consisting of O,N and S. In the case of bicycles, at least one of the rings is aromatic.Examples which may be mentioned are pyrid-4-yl, pyrid-3-yl,pyrimidin-5-yl, imidazol-1-yl and benzimidazol-5-yl.

2-7C-Heterocycloalkyl represents a—if desired substituted—monocyclicsaturated or partially saturated hydrocarbon which contains 2 to 7carbon atoms and at least one ring nitrogen atom; in addition, one ormore carbon atoms may be replaced by ring heteroatoms selected from thegroup consisting of O, N and S. Examples which may be mentioned arepiperid4-yl, piperazin-1-yl, pyrrolidin-2-yl, pyrrolidin-3-yl,imidazolidin-1-yl, imidazolidin-2-yl, lmidazolidin-4-yl andmorpholin-2-yl.

5-12C-Arylene represents a—if desired substituted—divalent mono- orbicyclic aromatic hydrocarbon radical having 5 to 12 carbon atoms, wherein the case of bicyclic aromatic hydrocarbon radicals at least one ofthe rings is aromatic. The free valencies can both be located at thearomatic, both at the nonaromatic or one at the aromatic and one at thenonaromatic ring. Examples which may be mentioned are 1,4-phenylene,1,3-phenylene, 1,4-naphthylene and 2,6-naphthylene.

5-12C-Heteroarylene represents an arylene radical as defined above inwhich 1 to 4 carbon atoms are replaced by heteroatoms selected from thegroup consisting of O, N and S. Examples which may be mentioned are2,5-furylene, 2,5-pyrrolylene, 4,2-pyridylene, 5,2-pyridylene,2,5-indolylene, 2,6-indolylene, 3,5-indolylene, 3,6-indolylene,3,5-indazolylene, 3,6-indazolylene, 2,5-benzofuranylene,2,6-quinolinylene and 4,2-thiazolylene.

3-8C-Cycloalkylene represents a—if desired substituted—divalentmonocyclic saturated or partially saturated hydrocarbon radical having 3to 8 carbon atoms. Examples which may be mentioned are the1,3-cyclopentylene, the 1,3-cyclohexylene and preferably the1,4-cyclohexylene radicals.

3-8C-Heterocycloalkylene represents a cycloalkylene radical as definedabove in which 1 to 3 carbon atoms are replaced by heteroatoms selectedfrom the group consisting of O, N and S. Examples which may be mentionedare the 1,4-piperidinylene, 1,4-piperazinylene, 2,5-pyrrolidinylene,4,2-imidazolidinylene and preferably the 4,1-piperidinylene radicals.

Preferred meanings of the groups X1 and X2 are amino, aminocarbonyl,amidino and guanidino.

By definition, the groups Z1 and Z2 are located between the groups B9and B11 (—B9-Z1-B11-) and B10 and B12 (—B10-Z2-B12-), respectively.Accordingly, in the divalent groupings mentioned by way of example (forexample 2,6-indolylene), the first number indicates the point ofattachment to the group B9 and B10, respectively, and the second numberindicates the point of attachment to the group B11 and B12,respectively.

The definitions of M, A3, A4, X1 and X2 contain chemical formulae, suchas, for example,

Here, bonds which are unattached on one side mean that the buildingblock is attached at this site to the remainder of the molecule. Bondswhich are unattached on both sides mean that this building block has aplurality of sites via which the building block can be attached to theremainder of the molecule.

In the context of this application, the term terminal nitrogen atommeans in each case a nitrogen atom in the groups designated X1, X2, Y1and Y2.

If the group X1 or X2 contains only one nitrogen atom, this nitrogenatom is the terminal nitrogen atom.

If the group X1 or X2 contains a plurality of nitrogen atoms, thenitrogen atom which is furthest from the atom by means of which the bondto the group B9 (B11) or B10 (B12) is established is the terminalnitrogen atom.

If the group Y1 or Y2 contains only one ring nitrogen atom, this ringnitrogen atom is the terminal nitrogen atom.

If the group Y1 or Y2 contains a plurality of ring nitrogen atoms, thering nitrogen atom which is furthest from the atom by means of which thebond to the group B9 or B10 is established is the terminal nitrogenatom.

According to the invention, the direct route between the nitrogen atomswhich act as terminal nitrogen atoms in the groups defined as X1 (Y1) orX2 (Y2) is considered to be the number of bonds which is obtained bycounting the bonds which represent the shortest possible connectionbetween the terminal nitrogen atoms.

The following example is meant to illustrate the determination of thenumber of bonds on the direct route between two terminal nitrogen atoms:

Here, the direct route comprises 34 bonds.

Suitable salts for compounds of the formula I—depending onsubstitution—are all acid addition salts or all salts with bases.Particular mention may be made of the pharmacologically acceptable saltsof inorganic and organic acids customarily used in pharmacy. Thosesuitable are, on the one hand, water-soluble and water-insoluble acidaddition salts with acids such as, for example, hydrochloric acid,hydrobromic acid, phosphoric acid, nitric acid, sulfuric acid, aceticacid, citric acid, D-gluconic acid, benzoic acid,2-(4-hydroxybenzoyl)benzoic acid, butyric acid, sulfosalicylic acid,maleic acid, lauric acid, malic acid, fumaric acid, succinic acid,oxalic acid, tartaric acid, embonic acid, stearic acid, toluenesulfonicacid, methanesulfonic acid or 3-hydroxy-2-naphthoic acid, where theacids are employed in salt preparation—depending on whether a mono- orpolybasic acid is concerned and depending on which salt is desired—in anequimolar quantitative ratio or one differing therefrom.

On the other hand, salts with bases are also suitable. Examples of saltswith bases which may be mentioned are alkali metal (lithium, sodium,potassium) or calcium, aluminum, magnesium, titanium, ammonium,meglumine or guanidinium salts, where here too the bases are employed insalt preparation in an equimolar quantitative ratio or one differingtherefrom.

Pharmacologically unacceptable salts which can be obtained initially asprocess products, for example in the preparation of the compoundsaccording to the invention on an industrial scale, are converted intopharmacologically acceptable salts by processes known to the personskilled in the art.

It is known to the person skilled in the art that the compoundsaccording to the invention, and also their salts, may contain varyingamounts of solvents, for example when they are isolated in crystallineform. The invention therefore also embraces all solvates and inparticular all hydrates of the compounds of the formula I, and also allsolvates and in particular all hydrates of the salts of the compounds ofthe formula I.

Compounds of the formula I which are to be emphasized are those in which

A1 and A2 are identical or different and are —C(O)—, —NH—, —O—,—C(O)—NH—, —NH—C(O)—, —O—C(O)—, —C(O)—O— or a bond,

A3 and A4 are identical or different and are —C(O)—, —O—, —NH—,—O—C(O)—, —C(O)—O—, —C(O)—NH—, —NH—C(O)— or a bond, or are selected fromthe group consisting of

where

E is —O— (oxygen), —S— (sulfur) or —CH₂— (methylene) and

T is the group —C(O)— or a bond,

A5 and A6 are Identical or different and are —C(O)—, —NH—, —O—,—C(O)—NH—, —NH—C(O)—, —O—C(O)—, —C(O)—O—, —NH—C(O)—NH— or a bond,

M is the following central building block

K1 is —B7-(C(O))_(m)—B9-X1, —B7-(C(O))_(m)—B9-Y1 or—B7-(C(O))_(m)—B9-Z1-B11-X1.

K2 is —B8-(C(O))_(p)—B10-X2, —B8-(C(O))_(p)—B10-Y2 or—B8-(C(O))_(p)—B10-Z2—B12-X2,

B1, B2, B3, B4, B5 and B6 are identical or different and are a bond or1-4C-alkylene,

B7, B8, B9, B10, B11 and B12 are identical or different and are a bondor 1-4C-alkylene,

m is 0 or 1,

p is 0 or 1,

X1 and X2 are Identical or different and are selected from the followinggroups

where

RB is 1-4C-alkyl,

Y1 and Y2 are identical or different and are piperid-4-yl, piperid-3-yl,piperazin-1-yl, piperazin-2-yl, morpholin-2-yl, pyrrolidin-2-yl,pyrrolidin-3-yl, imidazolidin-1-yl, imidazolidin-2-yl,imidazolidin-4-yl, 2-imidazolin-3-yl, 2-imidazolin-2-yl, imidazol-1-yl,imidazol-2-yl, imidazol-4-yl, pyrid-4-yl, pyrid-3-yl, pyridazin-4-yl,pyrimidin-5-yl, pyrimidin-4-yl, indol-3-yl, benzimidazol-4-yl orbenzimidazol-5-yl,

Z1 and Z2 are identical or different and are 1,4-phenylene,1,3-phenylene, 1,4-naphthylene, 2,6-naphthylene, 1,4-cyclohexylene,1,3-cyclohexylene, 1,3-cyclopentylene, 1,4-piperazinylene,4,1-piperidinylene, 1,4-piperidinylene, 2,5-pyrrolidinylene,4,2-imidazolidinylene, 2,5-furylene, 2,5-pyrrolylene, 4,2-pyridylene,5,2-pyridylene, 2,5-indolylene, 2,6-indolylene, 3,5-indolylene,3,6-indolylene, 3,5-indazolylene, 3,6-indazolylene, 2,6-quinolinylene,2,5-benzofuranylene or 4,2-thiazolylene,

where each arylene, heteroarylene, cycloalkylene, heterocycloalkylene,heteroaryl or heterocycloalkyl may additionally for its part besubstituted by one, two or three substituents selected from the groupconsisting of hydroxyl, halogen, nitro, cyano, amino, 1-4C-alkyl,1-4C-alkoxy, 1-4C-alkoxycarbonyl, 1-4C-alkylcarbonyloxy, carboxyl oraminocarbonyl,

and where on the direct route between the terminal nitrogen atoms 20 to40, preferably 25 to 40, bonds have to be present,

the salts of these compounds, and the N-oxides of thenitrogen-containing heteroaryls, heterocycloalkyls, heteroarylenes andheterocycloalkylenes, and their salts, where all those compounds areexcluded in which one or more of the variables B1, B2, B3, B4, B5, B6,B7, B8, B9, B10, B11 or may assume the meaning of a bond, resulting inthe direct linkage of two heteroatoms or carbonyl groups.

One embodiment of the compounds of the formula I which are to beemphasized is that in which

A1 and A2 are identical or different and are —C(O)—NH—, —C(O)— or abond,

A3 and A4 are identical or different and are selected from the groupconsisting of

where

T is the group —C(O)— or a bond,

A5 and A6 are identical or different and are —O—, —C(O)—, —C(O)NH—,—NH—C(O)— or —NH—C(O)—NH—,

M is the following central building block

K1 is —B7-(C(O))_(m)—B9-Y1 or —B7-(C(O))_(m)—B9-Z1-B11-X1,

K2 is —B8-(C(O))_(p)—B10-Y2 or —B8-(C(O))_(p)—B10-Z2-B12-X2,

B1 and B2 are identical or different and are a bond or methylene,

B3, B4, B5 and B6 are identical or different and are a bond or1-3C-alkylene,

B7, B8, B9 and B10 are identical or different and are a bond or1-4C-alkylene,

B11 and B12 are identical or different and are a bond or methylene,

m is 0,

p is 0,

X1 and X2 are identical or different and are selected from the followinggroups

Y1 and Y2 are imidazol-1-yl,

Z1 and Z2 are identical or different and are 5,2-pyridinylene,6-methyl-5,2-pyridinylene, 4,1-piperidinylene, 3,6-indazolylene,3,6-indolylene, 1,3-phenylene, 1,4-phenylene, 1,3-cyclohexylene or1,4-cyclohexylene,

and where on the direct route between the terminal nitrogen atoms 20 to40, preferably 25 to 40, bonds have to be present,

the salts of these compounds, and the N-oxides of nitrogen-containingheteroaryls, heteroarylenes and heterocycloalkylenes, and their salts,where all those compounds are excluded in which one or more of thevariables B1, B2, B3, B4, B5, B6, B7, B8, B9, B10, B11 or B12 may assumebond, resulting in the direct linkage of two heteroatoms or carbonylgroups.

Another embodiment of the compounds of the formula I which are to beemphasized is that in which

A1 and A2 are identical or different and are —C(O)—, —C(O)—NH—, —C(O)—O—or a bond,

A3 and A4 are identical or different and are 1,4-piperazinylene,1,4-piperidinylene, 1,4-cyclohexylene, 1,3-phenylene or a bond,

A5 and A6 are identical or different and are —C(O)—, —C(O)—NH—,—NH—C(O)— or —NH—C(O)—NH—,

M is the following central building block

K1 is —B7-(C(O))_(m)—B9-Y1 or —B7-(C(O))_(m)—B9-Z1-B11-X1

K2 is B8-(C(O))_(p)—B10-Y2 or —B8-(C(O))_(p),—B10-Z2-B12-X2,

B1 and B2 are identical or different and are a bond or methylene,

B3, B4, B5 and B6 are identical or different and are a bond or1-3C-alkylene,

B7, B8, B9 and B10 are identical or different and are a bond or1-4C-alkylene,

B11 and B12 are identical or different and are a bond or methylene,

m is 0,

p is 0,

X1 and X2 are identical or different and are selected from the followinggroups

Y1 and Y2 are imidazol-1-yl,

Z1 and Z2 are identical or different and are 5,2-pyridinylene,6-methyl-5,2-pyridinylene, 4,1-piperidinylene, 3,6-indazolylene,3,6-indolylene, 1,3-phenylene, 1,4-phenylene, 1,3-cyclohexylene or1,4-cyclohexylene,

and where on the direct route between the terminal nitrogen atoms 20 to40, preferably 25 to 40, bonds have to be present,

the salts of these compounds, and also the N-oxides of thenitrogen-containing heteroaryls, heteroarylenes andheterocycloalkylenes, and their salts, where all those compounds areexcluded in which one or more of the variables B1, B2, B3, B4, B5, B6,B7, B8, B9, B10, B11 or B12 may assume the meaning of a bond, resultingin the direct linkage of two heteroatoms or carbonyl groups.

Preferred compounds of the formula I are those in which

—B1-A1-B3-A3-B5-A5- and —B2-A2-B4-A4-B6-A6- are identical or differentfrom

M is the following central building block

K1 is —B7-(C(O))_(m)—B9-Z1-B11-X1,

K2 is B8-(C(O))_(p)—B10-Z2-B12-X2,

B7, B8, B9 and B10 are identical or different and are a bond ormethylene,

B11 and B12 are methylene,

m is 0,

p is 0,

X1 and X2 are amino,

Z1 and Z2 are identical or different and are 1,3-phenylene or1,4-phenylene,

and the salts of these compounds.

Particularly preferred compounds of the formula I are

1,5-Bis-{2-[4-[(4-aminomethylbenzylaminocarbonyl)piperazin-1-yl]-2-oxoethyl}-perhydro-1,5-diazocin-2,6-dione;

1,5-Bis-{2-[4-(3-(4-aminomethylphenyl)propionyl)piperazin-1-yl]-2-oxoethyl}perhydro-1,5-diazocin-2,6-dione;

1,5-Bis-{2-[4-(3-(3-aminomethylphenyl)propionyl)piperazin-1-yl]-2-oxoethyl}perhydro-1,5-diazocin-2,6-dione;

1,5-Bis-{2-[4-(2-(4-aminomethylphenoxy)acetyl)piperazin-1-yl]-2-oxoethyl}perhydro-1,5-diazocin-2,6-dione;

and the salts of these compounds.

The compounds of the formula I are constructed from a large number ofdivalent building blocks (M, A1, A2, A3, A4, A5, A6, B1, B2, B3, B4, B5,B6, B7, B8, B9, B10, B11, B12, Z1 and Z2). In principle they can besynthesized starting with any of these building blocks. If the compoundsof the formula I are constructed largely symmetrically, it is favorableto start the synthesis with the central building block M, whereas in thecase of predominantly asymmetrical compounds of the formula I asynthesis starting with one of the end groups K1 or K2 may beadvantageous.

Here, the building blocks are linked using always the same pattern,known per se to the person skilled in the art.

It Is known to the person skilled in the art that the compounds of theformula I can either be synthe sized building block by building block,or by initially constructing relatively large fragments consisting ofseveral individual building blocks, which can then be joined to give thecomplete molecule.

Owing to the meanings which the individual building blocks of thecompounds of the formula I can assume, amino [—NH—], ether [—O—],thioether [—S—], keto [—C(O)—], sulfonyl [—S(O)₂—], ester [—O—C(O)—,—C(O)—O—], amide [—C(O)—NH—, —NH—C(O)—], sulfonamide [—SO₂—NH—,—NH—SO₂—], carbamate [—NH—C(O)—O—, —O—C(O)—NH—], carbamide[—NH—C(O)—NH—] or carbonate bridges [—O—C(O)—O—] are present in thecompounds of the formula I.

How to prepare such bridges is known per se to the person skilled in theart; suitable methods and starting materials for their preparation aredescribed, for example, in March, Advanced Organic Chemistry, Reactions,Mechanisms and Structure, Third Edition, 1985, John Wiley & Sons.

Ether and thioether bridges can be prepared, for example, by the methodof Williamson.

Keto bridges can be introduced, for example, as a component ofrelatively large building blocks, such as, for example,1,3-dichloroacetone.

Sulfonyl bridges can be obtained, for example, by oxidation of thioetherbridges.

There is a large number of known methods for preparing ester bridges. Anexample which may be mentioned here is the reaction of acids withalcohols, preferably using H₂SO₄ or p-toluenesulfonic acid as catalyst;or with addition of a dehydrating agent, such as, for example, molecularsieve or a carbodiimide. Furthermore, the reaction of acyl chlorideswith alcohols may be mentioned here.

There is also a large number of known methods for preparing amidebridges. An example which may be mentioned here is the reaction of acylchlorides with primary or secondary amines. Furthermore, reference isalso made to all the methods which have been developed for peptidechemistry. Accordingly, it is possible to construct sulfonamide bridgesfrom sulfonyl chlorides and primary or secondary amines.

Carbamate bridges can be prepared, for example, by reactingchloroformates with amines. The chloroformates for their part can besynthesized from alcohols and phosgene. A further variant forconstructing carbamate bridges is the addition of alcohols toisocyanates.

Similarly to the carbamate bridges, it is possible to prepare carbonatebridges starting from chloroformates, by reaction with alcohols (insteadof amines).

Carbamide bridges can be prepared, for example, by reacting isocyanateswith amines.

The preparation of compounds of the formula I may be shown in anexemplary manner using the reaction scheme below. Other compounds of theformula I can be prepared analogously, or by using the abovementionedmethods known per se to the person skilled in the art.

Reaction scheme 1 shows an example of the synthesis of a compound of theformula I.

It is also possible to convert compounds of the formula I byderivatization into other compounds of the formula I. Thus, for example,compounds of the formula I having a nitrogen-containing heteroaryl,heteroarylene, heterocycloalkyl or heterocycloalkylene building blockcan be converted by oxidation into the corresponding N-oxides.

The N-oxidation is carried out in a manner which is likewise known tothe person skilled in the art, for example using hydrogen peroxide inmethanol or m-chloroperoxybenzoic acid in dichloromethane at roomtemperature. Which reaction conditions are required in the particularcase for carrying out the process is known to the person skilled in theart owing to his expert knowledge.

It is furthermore known to the person skilled in the art that if thereare a number of reactive centers on a starting material or intermediate,it may be necessary to block one or more reactive centers temporarily byprotective groups in order to allow a reaction to proceed specificallyat the desired reaction center. A detailed description of the use of alarge number of proven protective groups is found, for example, in T. W.Greene, Protective Groups in Organic Synthesis, John Wiley & Sons, 1991.

The isolation and purification of the substances according to theinvention is carried out in a manner known per se, for example bydistilling off the solvent under reduced pressure and recrystallizingthe resulting residue from a suitable solvent or subjecting it to one ofthe customary purification methods, such as, for example, columnchromatography on a suitable support material.

Salts are obtained by dissolving the free compound in a suitable solvent(for example a ketone, such as acetone, methyl ethyl ketone or methylisobutyl ketone, an ether, such as diethyl ether, tetrahydrofuran ordioxane, a chlorinated hydrocarbon, such as methylene chloride orchloroform, or a low-molecular-weight aliphatic alcohol, such as ethanolor isopropanol) which contains the desired acid or base, or to which thedesired acid or base is then added. The salts are obtained by filtering,reprecipitating, precipitating with a nonsolvent for the addition saltor by evaporating the solvent. Salts obtained can be converted byalkalization or by acidification into the free compounds, which in turncan be converted into salts. In this way, pharmacologically unacceptablesalts can be converted into pharmacologically acceptable salts.

The examples below serve to illustrate the invention in more detailwithout restricting it. Likewise, further compounds of the formula I,whose preparation is not explicitly described, can be prepared in ananalogous manner or in a manner familiar per se to the person skilled inthe art using customary process techniques.

In the examples below, the abbreviation RT stands for room temperature,h for hours, min. for minutes, DMF for dimethylformamide and HBTU forO-(benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexa-fluorophosphate.The compounds mentioned in the examples and their salts are thepreferred subject of the invention.

EXAMPLES End Products

1.1,5-bis-{2-[4-(4-Aminomethylbenzylaminocarbonyl)piperazin-1-yl]-2-oxoethyl}perhydro-1,5-diazocin-2,6-dioneDihydrochloride

0.2 g of1,5-bis-{2-[4-(4-tert-butyloxycarbonylaminomethylbenzylaminocarbonyl)piperazin-1-yl]-2-oxoethyl}-perhydro-1,5-diazocin-2,6-dione(starting material A1) is suspended in 2 ml of dichloromethane and thenadmixed with 2 ml of trifluoroacetic acid. The mixture is stirred at RTovernight, and 2 ml of a solution of HCl in dioxane are then added. Themixture is concentrated to dryness using a rotary evaporator. Theresidue is twice triturated with ether and the solvent decanted off. Theresidue is then dried under high vacuum. This gives 0.17 g of the titlecompound of m.p. from 90° C. (decomposition). The mass spectrum showsthe molecular peak MH⁺ at 719 Da.

2.1,5-bis-{2-[4-(3-(4-aminomethylphenyl)proplonyl)piperazin-1-yl]-2-oxoethyl}perhydro-1,5-diazocin-2,6-dioneDihydrochloride

The title compound is prepared in analogy to example 1 from 0.08 g1,5-bis-{2-[4-(3-(4-tert-butoxycarbonylaminomethylphenyl)propionyl)piperazin-1-yl]-2-oxoethyl}perhydro-1,5-diazocin-2,6-dione(starting material B1) in 2 ml dichloromethane/2 ml trifluoroaceticacid. Yield: 0.055 g; the mass spectrum shows the molecular peak MH⁺ at717 Da.

3.1,5-bis-{2-[4-(3-(3-aminomethylphenyl)proplonyl)piperazin-1-yl]-2-oxoethyl}perhydro-1,5-diazocin-2,6-dioneDihydrochloride

The title compound is prepared from 0.083 g1,5-bis-{2-[4-(3-(3-tert-butoxycarbonylaminomethylphenyl)-propionyl)piperazin-1-yl]-2-oxoethyl}-1,5-diazocin-2,6-dione(starting material C1) as described in example 1. Yield: 0.063 g; massspectrum: MH⁺=717 Da.

4.1,5-bis-{2-[4-(2-(4-Aminomethylphenoxy)acetyl)perazin-1-yl]-2-oxoethyl}perhydro-1.5-diazocin-2,6-dioneDihydrochloride

The title compound is prepared from 0.142 g1,5-bis-{2-[4-(2-(4-tert-butoxycarbonylaminomethylphenoxyyacetyl)piperazin-1-yl-]-2-oxoethyl}-1,5-diazocin-2,6-dione(starting material D1) as described in example 1. Yield: 0.115 g; massspectrum: MH⁺=721 Da.

Starting Materials

A1.1,5-bis-{2-[4-(4-tert-Butyloxycarbonylaminomethylbenzylaminocarbonyl)piperazin-1-yl]-2-oxoethyl}perhydro-1,5-diazocin-2,6-dione

A mixture of 0.538 ml of triethylamine in 10 ml of DMF is mixedsuccessively with 0.4 g of(5-carboxy-methyl-2,6-dioxoperhydro-1,5-diazocin-1-yl)acetic acid(starting material A2) and 1.23 g of HBTU, with stirring. After onehour, 1.13 g of1-[4-(tert-butyloxycarbonylaminomethyl)benzylamino-carbonyl]piperazine(starting material A4) are added, and the mixture is stirred overnight.The mixture is diluted with dichloromethane and admixed with water.After phase separation, the organic phase is washed with 1N hydrochloricacid solution, 1N aqueous sodium hydroxide solution and water. Theorganic phase is concentrated and the residue is triturated withacetone/ethyl acetate, filtered off with suction and recrystallized frommethanol/ether. Drying under reduced pressure gives 0.75 g of the titlecompound of m.p. 156-160° C. The mass spectrum shows the molecular peakMH⁺ at 919 Da.

A2. (5-Carboxymethyl-2,6-dioxoperhydro-1,5-diazocin-1-yl)acetic Acid

1.4 g oftert-butyl-(5-tert-butoxycarbonylmethyl-2,6-dioxoperhydro-1,5-diazocin-1-yl)acetate(starting material A3) are dissolved in 6 ml of dichloromethane andadmixed with 6 ml of trifluoroacefic acid. The mixture is stirredovernight and then concentrated using a rotary evaporator, and theresidue is triturated with ethyl acetate/petroleum ether (1:1). Theresidue is filtered off with suction and dried under reduced pressure.This gives 0.89 g of the title compound of m.p. from 250° C.(decomposition). The mass spectrum shows the molecular peaks MH⁺ andMNH₄ ⁺ at 259 and 276 Da.

A3. tert-Butyl(5-tert-butoxycarbonylmethyl-2,6-dioxoperhydro-1,5-diazocin-1-yl)acetate

3.3 g of perhydro-1,5-diazocin-2,6-dione are suspended in 30 ml ofabsolute DMF, and 732 mg of sodium hydride (80%) are then added. Themixture is stirred at RT for 15 min and then cooled to 0° C., and 3.76ml of tert-butyl bromoacetate are then added. The mixture is stirred at0° C. for 15 min and at RT for 30 min, and is then once again cooled to0° C., and another 732 mg of sodium hydride (80%) are added. After 15min, a further 3.76 ml of tert-butyl bromoacetate are added using apipette, the ice bath is removed after 15 min and the mixture stirred atRT overnight. The mixture is then diluted with dichloromethane, water isadded, and the phases are then separated and the organic phase is washedtwice with water. The organic phase is dried over MgSO₄ andconcentrated, and the residue is dried under high vacuum andrecrystallized from n-hexane. This gives 2.5 g of the title compound ofm.p. 180° C. The mass spectrum shows the molecular peaks MH⁺ and MNH₄ ⁺at 371 and 388 Da.

A4.1-[4-(tert-Butyloxycarbonylaminomethyl)benzylaminocarbonyl]piperazine

41.7 g of benzyl4-[4-(tert-butyloxycarbonylaminomethyl)benzylaminocarbonyl]piperazine-1-carboxylate(starting material A5) in 1.0 l of methanol are hydrogenated overpalladium/carbon (5%) for 4 h. The catalyst is filtered off and thesolvent is removed, giving 30.3 g of the title compound as a colorlessoil.

A5. Benzyl4-[4-(tert-Butyloxycarbonylaminomethyl)benzylaminocarbonyl]piperazine-1-carboxylate

At 0° C., 25.0 g (106 mmol) of4-(tert-butyloxycarbonylaminomethyl)benzylamine in 150 ml ofdichloromethane are added dropwise to a solution of 22.4 g (111 mmol) of4-nitrophenyl chloroformate in 200 ml of dichloromethane, and themixture is stirred for 10 min. 15.6 ml (111 mmol) of triethylamine arethen added dropwise, and the mixture is stirred at RT for 1.5 h. At 0°C., initially 24.5 g (111 mmol) of benzyl piperazine-1-carboxylate in 80ml of dichloromethane and then 15.6 ml (111 mmol) of triethylamine areadded dropwise. The mixture is stirred at RT for 16 h. The solvent isremoved from the reaction mixture and the crude product ischromatographed over silica gel (toluene/ethyl acetate=1:1).Crystallization from diisopropyl ether gives 41.7 g of the titlecompound as a colorless solid of m.p. 108-112° C.

B1.1,5-bis-{2-[4-(3-(4-tert-Butoxycarbonylaminomethylphonyloproplonyl)pirerazin-1-yl]-2-oxoethyl}perhydro-1,5-diazocin-2,6-dione

A mixture of 0.3 ml of ethyldiisopropylamine in 4 ml of DMF is mixedsuccessively with 0.15 g of(5-carboxymethyl-2,6-dioxoperhydro-1,5-diazocin-1-yl)acetic acid(starting material A2) and 0.463 g of HBTU with stirring. After 10 min,0.404 g of1-[3-(4-tert-butyloxycarbonylaminomethyl-phenyl)propionyl)piperazine(starting material B2) are added, and the mixture is stirred for 3 h.The mixture is diluted with dichloromethane and admixed with water.After phase separation, the organic phase is washed with 1N hydrochloricacid solution, 1N aqueous sodium hydroxide solution and water. Afterdrying over magnesium sulfate, the organic solution is concentrated andthe residue is chromatographed over silica gel(dichloromethane/methanol=9:1). Concentration of the pure fractions anddrying in vacuo gives 0.29 g of the title compound as a colourlesspowder. The mass spectrum shows the molecular peaks MH⁺ and MNa⁺ at 917and 939 Da.

B2. 1-[3-(4-tert-Butyloxycarbonylaminomethylphenyl)propionyl)piperazine

3.64 g of1-benzyloxycarbonyl-4-[3-(4-tert-butyloxycarbonylaminomethylphenyl)propionyl]piperazine(starting material B3), dissolved in 100 ml methanol are hydrogenatedover palladiumicarbon (10%) for 3 h. The catalyst is filtered off andthe solvent is removed in vacuo, giving 2.55 g of the title compound.The mass spectrum shows the molecular peak MH⁺ at 348 Da.

B3.1-Benzyloxycarbonyl-4-[3-(4-tert-butyloxycarbonylaminomethylphenyl)propionyl]-piperazine

A mixture of 11.4 ml of ethyldiisopropylamine in 20 ml of DMF is mixedsuccessively with 3.11 g of3-(4-tert-butyloxycarbonylaminomethylphenyl)propionic acid (startingmaterial B4) and 4.64 g HBTU, with stirring. After ten minutes 2.45 g of1-benzyloxycarbonylpiperazine are added and the mixture is stirred at RTfor 5 h. The mixture is diluted with ethyl acetate and water. Afterphase separation, the organic phase is washed with 1N hydrochloric acidsolution, 1N aqueous sodium hydroxide solution and water. After dryingover magnesium sulfate, the organic solution is concentrated and theresidue is chromatographed over silica gel (petrolether/ethylacetate/acetone 4:5:1). Concentration of the pure fractions and dryingin vacuo gives 3.91 g of the title compound as a yellowish powder. Themass spectrum shows the molecular peak MH⁺ at 481.8 Da.

B4. 3-(4-tert-Butyloxycarbonylaminomethylphenyl)propionic Acid

4.65 g of methyl 3-4-aminomethylphenyl)propionate hydrochloride(starting material B5) and 6.17 ml of triethylamine are mixed in 20 mlof dichloromethane. To this mixture, a solution of 4.62 g ofdi-tert-butyl-dicarbonate in 10 ml of dichloromethane is added slowly at0° C. with stirring. Stirring is continued 1 h at 0° C. and 3 h at RT.Then the reaction mixture is washed twice with 1N hydrochloric acidsolution, with sodium hydrogen carbonate solution and water. Afterdrying over magnesium sulfate, the solvent is removed and the residue(5.6 g) is dissolved in 50 ml of tetrahydrofurane. 13.4 ml of 2N aqueoussodium hydroxide solution is added and the mixture is stirred overnight,neutralized with 6.7 ml of 4N hydrochloric acid solution and the organicsolvent is distilled off. The white precipitate is filtered by suction,washed with water and dried to give 4.65 g of the title compound. Themass spectrum shows the molecular peak MNH₄ ⁺ at 297 Da.

B5. Methyl 3-(4-Aminomethylphenyl)propionate Hydrochloride

5.6 g of methyl 4-(hydroxyimino-methyl)cinnamate (starting material B6)are dissolved in a mixture of 170 ml of methanol and 50 ml of aceticacid and hydrogenated over 0.5 g palladium/carbon (10%) for four hours.The catalyst is filtered off and the solvents are removed. The residueis stirred with ether and then a solution of hydrogen chloride In etherIs added. The white precipitate is filtered by suction, washed withether and dried in vacuo to give 4.65 g of the title compound. The massspectrum shows the molecular peak MH⁺ at 194 Da.

B6. Methyl 4-(Hydroxyimino-methyl)cinnamate

4.0 g of methyl 4-formylcinnamate are dissolved in 40 ml methanol andthen 1.6 g hydroxylamine-hydrochloride and 1.9 g sodium acetate areadded. The mixture is stirred overnight and then diluted with 300 mlwater. The precipitate is filtered by suction, dried in vacuo andcrystallized from ethyl acetate/petrolether. This gives 3.56 9 of thetitle compound. The mass spectrum shows the molecular peak MH⁺ at 206Da.

C1.1,5-bis-{2-[4-3-(3-tert-Butoxycarbonylaminomethylphenyl)propionyl)piperazin-1-yl]-2-oxoethyl}perhydro-1,5-diazocin-2,6-dione

0.358 g of 3-(3-tert-butyloxycarbonylaminomethylphenyl)propionic acid(starting material C2), 0.445 ml of triethylamine and 0.485 mg of HBTUare successively dissolved in 3 ml of DMF. After stirring for tenminutes 0.3 9 of1,5-bis-[2-oxo-2-(piperazin-1-yl)-ethyl]perhydro-1,5-diazocin-2,6-dionedihydrochloride (starting material C5) are added and the mixture isstirred for 24 h at RT. The mixture is diluted with dichloromethane andadmixed with water. After phase separation, the organic phase is washedwith 1N hydrochloric acid solution, 1N aqueous sodium hydroxide solutionand water. After drying over magnesium sulfate, the organic solution isconcentrated and the residue is chromatographed over silica gel(dichloromethane/methanol=98:2). Concentration of the pure fractions anddrying in vacuo gives 0.1 g of the title compound as a colorless powder.The mass spectrum shows the molecular peaks MH⁺ and MNa⁺ at 917 and 939Da.

C2. 3-(3-tert-Butyloxycarbonylaminomethylphenyl)propionic Acid

To 3.6 g of methyl3-(3-tert-butyloxycarbonylaminomethylphenyl)propionate (C3) in 36 ml oftetrahydrofurane 14.8 ml of 1N aqueous sodium hydroxide solution areadded and the mixture is stirred at RT for 2 days. After neutralizationwith 14.8 ml 1N hydrochloric acid solution and dilution with water themixture is extracted three times with ethyl acetate. The combinedextracts are dried over magnesium sulfate, filtered and the solventremoved in vacuo to give 3.5 g of the title compound as a brownish oilwhich solidifies on standing in a refrigerator. The mass spectrum showsthe molecular peak MNH₄ ⁺ at 297 Da.

C3. Methyl 3-(3-tert-Butyloxycarbonylaminomethylphenyl)proplonate

6.9 g of methyl 3-(3-aminomethylphenyl)propionate hydroacetate (startingmaterial C4) and 9.46 ml of triethylamine are mixed in 75 ml ofdichloromethane. To this mixture, 5.94 g of di-tert-butyl-dicarbonateare added in portions with stirring. Stirring is continued for 5 h atRT. Then the reaction mixture is washed twice with 1N hydrochloric acidsolution, with sodium hydrogen carbonate solution and water. Afterdrying over magnesium sulfate, the solvent is removed and the residue ischromatographed over silica gel (petrolether/ethyl acetate=7:3).Concentration of the pure fractions and drying in vacuo gives 3.93 g ofthe title compound as an oil. The mass spectrum shows the molecular peakMNH₄ ⁺ at 311 Da.

C4. Methyl 3-(3-Aminomethylphenyl)proplonate Hydroacetate

8.22 g of methyl 3-(3-cyanophenyl)acrylate are hydrogenated in a mixtureof 80 ml methanol and 5 ml acetic acid over 0.8 g palladium/carbon(10%)for 20 h. The catalyst is filtered off and the solvent is removed. Theresidue is coevaporated three times with toluene and dried in vacuo togive 7.5 g of the title compound. The mass spectrum shows the molecularpeak MH⁺ at 194 Da.

C5.1,5-bis-[2-oxo-2-piperazin-1-yl)-ethyl]perhydro-1,5-diazocin-2,6-dioneDihydrochloride

To 2.95 g of1,5-bis-[2-oxo-2-(4-tert-butyloxycarbonylpiperazin-1-yl)ethyl]perhydro-1,5-diazocin-2,6-dione(starting material C6) in 10 ml dichloromethane 10 ml of trifluoroaceticacid are added with stirring. After four days the mixture is dilutedwith ether and the title compound is precipitated by addition of asolution of hydrogen chloride in ether. The precipitate is filtered bysuction, washed with ether and dried in vacuo to give 2.2 g. The massspectrum shows the molecular peak MH⁺ at 395 Da.

C6.1,5-bis-[2-oxo-2-(4-tert-Butyloxycarbonylpiperazin-1-yl)ethyl]perhydro-1,5-diazocin-2,6-dione

2.5 ml of ethyidiisopropylamine and 4.62 g HBTU are successively addedto a solution of 1.5 g of(5-carboxymethyl-2,6-dioxoperhydro-1,5diazocin-1-yl)acetic acid(starting material A2) in 10 ml dimethyifonmamide with stirring. After15 minutes 2.27 g 1-tert-butoxycarbonylpiperazine are added and themixture is stirred overnight at RT. After dilution with ethyl acetateand water, the organic phase is separated and washed twice with 1Naqueous sodium hydroxide solution and 1N hydrochloric acid solution andfinally with sodium-hydrogen carbonate solution and brine. After dryingover magnesium sulfate and filtration, the solvent is removed and theresidue is dried under reduced pressure to give 3.1 g of the titlecompound. The mass spectrum shows the molecular peaks MH⁺ and MNa⁺ at595 and 617 Da.

D1.1,5-bis-{2-[4-(2-(4-tert-Butoxycarbonylaminophenoxy)-acetyl)piperazin-1-yl]-2-oxoethyl}-1,5-diazocin-2,6-dione

0.5 ml of triethylamine and 0.485 g HBTU are successively added to asolution of 0.36 g of 2-(4-tert-butoxycarbonylaminomethyl-phenoxy)aceticacid (starting material D2) in 3 ml dimethylformamide with stirring.After 15 min 0.3 g of1,5-bis-[2-oxo-2-(piperazin-1-yl)-ethyl]perhydro-1,5-diazocin-2,6-dione-dihydrochloride(starting material C5) are added and the mixture is stirred for 48 h atRT. The mixture is diluted with dichloromethane and admixed with water.After phase separation, the organic phase is washed twice with 1Naqueous sodium hydroxide solution and 1N hydrochloric acid solution andfinally with sodium hydrogen carbonate solution and brine. After dryingover magnesium sulfate, the organic solution is concentrated and theresidue is chromatographed over silica gel(dichloromethane/methanol=88:12). Concentration of the pure fractionsand drying in vacuo gives 0.175 g of the title compound as a powder. Themass spectrum shows the molecular peaks MH⁺ and MNa⁺ at 921 and 943 Da.

D2. 2-(4-tert-Butoxycarbonylaminomethyl-phenoxy)acetic Acid

1 g of methyl 2-(4-tert-butoxycarbonylaminomethyl-phenoxy)acetate(starting material D3) is saponified with 4.1 ml 1N aqueous sodiumhydroxide solution in 10 ml tetrahydrofurane as described for startingmaterial C2. Yield: 0.7g; the mass spectrum shows the molecular peakMNa⁺ at 304 Da.

D3. Methyl 2-(4-tert-butoxycarbonylaminomethyl-phenoxy)acetate

21.1 ml of triethylamine are added to a suspension of 14.1 g methyl2-(4-aminomethyl-phenoxy)-acetate hydrochloride (starting material D4)in 150 ml dichloromethane with stirring, then a solution of 13.93 g ofdi-tert-butyl-dicarbonate in 30 ml dichloromethane is added dropwise andthe mixture is stirred overnight at RT. The reaction mixture is washedtwice with 1N aqueous sodium hydroxide solution and 1N hydrochloric acidsolution and finally with sodium hydrogen carbonate solution and brine.After drying over magnesium sulfate and filtration, the solvent isremoved and the residue is dried under reduced pressure to give 16.7 gof the title compound. The mass spectrum shows the molecular peak MNH₄ ⁺at 313 Da.

D4. Methyl 2-(4-aminomethyl-phenoxy)acetate Hydrochloride

A solution of 18.3 g of methyl 2-(4-hydroxyiminomethyl-phenoxy)acetate(starting material D5) and 45 ml acetic acid in 150 ml methanol ishydrogenated over 2 g palladium/carbon(10%) for 5 h. The catalyst isfiltered off and the solvent is removed. The residue is coevaporatedthree times with toluene and then triturated with a solution of hydrogenchloride in ether. The precipitate formed is filtered by suction, washedseveral times with ether and dried under reduced pressure to give 15.9 gof the title compound. The mass spectrum shows the molecular peak MH⁺ at196 Da.

D5. Methyl 2-(4-Hydroxyiminomethyl-phenoxy)acetate

24.4 g of methyl 2-(4-formylphenoxy)acetate are dissolved in 300 mlmethanol and then 9.6 g hydroxylamine hydrochloride and 11.33 g sodiumacetate are added. The mixture is stirred overnight, then diluted with1.2 l water and cooled. The precipitate is filtered off by suction,washed with cold water and dried under reduced pressure. This gives18.43 g of the title compound. The mass spectrum shows the molecularpeak MH⁺ at 210 Da.

Commercial Utility

As tryptase inhibitors, the compounds according to the invention haveuseful pharmacological properties which make them commerciallyutilizable. Human tryptase is a serine protease which is the mainprotein in human mast cells. Tryptase comprises eight closely relatedenzymes (α1, α2, β1a, β1b, β2, β3, mMCP-7-like-1, mMCP-7-like-2; 85 to99% sequence identity) (cf. Miller et al., J. Clin. Invest. 84 (1989)1188-1195; Miller et al., J. Clin. Invest. 86 (1990) 864-870;Vanderslice et al., Proc. Natl. Sci., USA 87 (1990) 3811-3815; Pallaoroet al., J. Biol. Chem. 274 (1999) 3355-3362). However, only thep-tryptases (Schwartz et al., J. Clin. Invest. 96 (1995) 2702-2710;Sakai et al., J. Clin. Invest. 97 (1996) 988-995) are activatedintracellularly and stored in catalytically active form in secretorygranules. Compared with other known serine proteases, such as, forexample, trypsin or chymotrypsin, tryptase has some special properties(Schwartz et al., Methods Enzymol. 244, (1994), 88-100; G. H. Caughey,“Mast cell proteases in immunology and biology”. Marcel Dekker, Inc.,New York, 1995). Tryptase from human tissue has a noncovalenuy-linkedtetrameric structure which has to be stabilized by heparin or otherproteoglycanes to be proteolytically active. Together with otherinflammatory mediators, such as, for example, histamine andproteoglycanes, tryptase is released when human mast cells areactivated. Because of this, tryptase is thought to play a role in anumber of disorders, in particular in allergic and inflammatorydisorders, firstly because of the importance of the mast cells in suchdisorders and secondly since an increased tryptase concentration wasobserved in a number of disorders of this type. Thus, tryptase isassociated, inter alia, with the following diseases: acute and chronic(in particular inflammatory and allergen-induced) airway disorders ofvarious origins (for example bronchitis, alergic bronchitis, bronchialasthma, COPD); interstitial lung disorders; disorders based on allergicreactions of the upper airways, (pharynx, nose) and the adjacent regions(for example paranasal sinuses, conjunctivae), such as, for exampleallergic conjunctivitis and allergic rhinitis; disorders of thearthritis type (for example rheumatoid arthritis); autoimmune disorders,such as multiple sclerosis; furthermore periodontitis, anaphylaxis,interstitial cystitis, dermatitis, psoriasis, sclerodermia/systemicsclerosis, inflammatory intestinal disorders (Crohn's disease,inflammatory bowel disease) and others. In particular, tryptase seems tobe connected directly to the pathogenesis of asthma (Caughey, Am. J.Respir. Cell Mol. Biol. 16 (1997), 621-628; R. Tanaka, “The role oftryptase in allergic inflammation” in: Protease Inhibitors, IBC LibrarySeries, 1979, Chapter 3.3.1-3.3.23).

A further subject of the invention relates to the compounds according tothe invention for use in the treatment and/or prophylaxis of diseases,in particular the diseases mentioned.

The invention likewise relates to the use of the compounds according tothe invention for preparing medicaments which are employed for thetreatment and/or prophylaxis of the diseases mentioned.

Medicaments for the treatment and/or prophylaxis of the diseasesmentioned, which contain one or more of the compounds according to theinvention, are furthermore a subject of the invention.

The medicaments are prepared by processes which are known per se andfamiliar to the person skilled in the art. As medicaments, the compoundsaccording to the invention (=active compounds) are either employed assuch, or preferably in combination with suitable pharmaceuticalexcipients, for example in the form of tablets, coated tablets,capsules, suppositories, patches, emulsions, suspension, gels orsolutions, the active compound content advantageously being between 0.1and 95%.

The person skilled in the art is familiar on the basis of his/her expertknowledge with the excipients which are suitable for the desiredpharmaceutical formulations. In addition to solvents, gel-formingagents, ointment bases and other active compound vehicles, it ispossible to use, for example, antioxidants, dispersants, emulsifiers,preservatives, solubilizers or permeation promoters.

For the treatment of disorders of the respiratory tract, the compoundsaccording to the invention are preferably also administered byinhalation. For this purpose, they are either administered directly as apowder (preferably in micronized form) or by nebulization of solutionsor suspensions which contain them. With respect to the preparations andadministration forms, reference is made, for example, to the details inEuropean Patent 163 965.

For the treatment of dermatoses, the compounds according to theinvention are in particular used in the form of those medicaments whichare suitable for topical administration. For the preparation of themedicaments, the compounds according to the invention (=activecompounds) are preferably mixed with suitable pharmaceutical excipientsand further processed to give suitable pharmaceutical formulations.Suitable pharmaceutical formulations which may be mentioned are, forexample, powders, emulsions, suspensions, sprays, oils, ointments, fattyointments, creams, pastes, gels or solutions.

The medicaments according to the invention are prepared by processesknown per se. The dosage of the active compounds in the case of systemictherapy (p.o. or i.v.) is between 0.1 and 10 mg per kilogram per day.

Biological Investigations

The documented pathophysiological effects of mast cell tryptase arecaused directly by the enzymatic activity of the protease. Accordingly,they are reduced or blocked by inhibitors which inhibit the enzymaticactivity of the tryptase. A suitable measure for the affinity of areversible inhibitor to the target protease is the equilibriumdissociation constant K_(i) of the enzyme-inhibitor complex. This K_(i)value can be determined via the effect of the inhibitor on thetryptase-induced cleavage of a chromogenic peptide-p-nitroanilidesubstrate or a fluorogenic peptide-aminomethylcoumarin substrate.

Methodology

The dissociation constants for the tryptase-inhibitor complexes aredetermined under equilibrium conditions in accordance with the generalproposals of Bieth (Bieth J G, Pathophysiological Interpretation ofkinetic constants of protease inhibitors, Bull. Europ. Physiopath. Resp.16:183-195, 1980) and the methods of Sommerhoff et al. (Sommerhoff C Pet al., A Kazal-type inhibitor of human mast cell tryptase: Isolationfrom the medical leech Hirudo medicinalis, characterization, andsequence analysis, Biol. Chem. Hoppe-Seyler 375: 685-694, 1994).

Human tryptase is isolated from lung tissue or prepared recombinantly;the specific activity of the protease, determined by titration, isusually greater than 85% of the theoretical value. In the presence ofheparin (0.1-50 μg/ml) for stabilizing the protease, constant amounts ofthe tryptase are incubated with increasing amounts of the inhibitors.After an equilibrium between the reaction partners has formed, theremaining enzyme activity after addition of the peptide-p-nitroanilidesubstrate tos-Gly-Pro-arg-pNA is determined and the cleavage of thelatter is monitored at 405 nm for 3 min. Alternatively, the remainingenzymatic activity can also be determined using fluorogenic substrates.The apparent dissociation constants K_(iapp) (i.e. in the presence ofsubstrate) are subsequently determined by adapting the enzyme rates tothe general equation for reversible inhibitors (Morrison J F, Kineticsof the reversible inhibition of enzymecatalyzed reactions bytight-binding inhibitors, Biochim. Biophys. Acta 185, 269-286, 1969)using non-linear regression:

V ₁ V ₀=1−{E _(t) +I _(t) +K _(iapp)−[(E _(t) +I _(t) +K _(iapp))²−4E_(t) I _(t)]^(½)}/2E _(t)

V₁ and V₀ are the rates in the presence and absence, respectively, ofthe inhibitor, and E_(t) and I_(t) are the tryptase and inhibitorconcentrations, respectively.

The apparent dissociation constants determined for the compoundsaccording to the invention are shown in Table A below, where the numbersof the compounds correspond to the numbers of the compounds in theexamples.

Table A Inhibition of human tryptase Compound K_(lapp) (μM) 1 0.0026 20.0012 3 0.0033 4 0.0008

What is claimed is:
 1. A compound of formula I

in which —B1-A1-B3-A3-B5-A5- and —B2-A2-B4-A4-B6-A6- are identical andare selected from the group consisting of

M is the following central building block

K1 is —B7-(C(C))_(m)—B9-Z1-B11-X1, K2 is —B8-(C(O))_(p)—B10-Z2-B12-X2,B7 and B8 are identical and are a bond or methylene, B9 and B10 areidentical and are a bond or methylene, B11 and B12 are methylene, m is0, p is 0, X1 and X2 are amino, Z1 and Z2 are identical and are1,3-phenylene or 1,4-phenylene, or a salt thereof.
 2. A compound offormula I according to claim 1, selected from the group1,5-bis-{2-[4-[(4-aminomethylbenzylaminocarbonyl)piperazin-1-yl]-2-oxoethyl}-perhydro-1,5-diazocin-2,6-dione;1,5-bis-{2-[4-(3-(4-aminomethylphenyl)propionyl)piperazin-1-yl]-2-oxoethyl}-perhydro-1,5-diazocin-2,5-dione;1,5-bis-{2-[4-(3-(3-aminomethylphenyl)propionyl)piperazin-1-yl]-2-oxoethyl}-perhydro-1,5-diazocin-2,6-dione;1,5-bis-{2-[4-(2-(4-aminomethylphenoxy)acetyl)piperazin-1-yl]-2-oxoethyl}-perhydro-1,5-diazocin-2,6-dione;or a salt thereof.
 3. A method for treating an allergic or inflammatorydisorder which comprises: administering the compound of claim 1 to apatient in need thereof wherein the allergic or inflammatory disorder isselected from the group consisting of bronchitis, allergic bronchitis,asthma, bronchial asthma, COPD, allergic conjunctivitis, allergicrhinitis, arthritis, rheumatoid arthritis, periodontitis, anaphylaxis,interstitial cystitis, dermatitis, psoriasis, sclerodermatitis, Crohn'sdisease and inflammatory bowel disease, wherein the allergic orinflammatory disorder may be acute or chronic.
 4. A pharmaceuticalcomposition comprising one or more compounds of formula I as claimed inclaim 1, together with pharmaceutically acceptable auxiliaries and/orexcipients.
 5. A method of treating an allergic or inflammatory disorderaccording to claim 3, wherein the allergic or inflammatory disorder isselected from the group consisting of bronchitis, allergic bronchitis,asthma, bronchial asthma, and COPD, wherein the allergic or inflammatorydisorder may be acute or chronic.